Field of the Invention
The present invention relates to medical devices and methods for treating, reducing, or preventing stenosis using non-thermal irreversible electroporation. Embodiments of the present invention provide balloon catheter devices for treating or preventing stenosis comprising a plurality of electrodes for selectively and irreversibly electroporating a portion of the inner circumference of a tubular structure within the body. Such devices, systems and methods are particularly useful for treating asymmetrical stenosis.
Description of Related Art
Atherosclerosis is the main cause of heart attack, stroke and gangrene of the extremities. See Burt H M, Hunter W L (2006), Drug-eluting stents: a multidisciplinary success story, Adv Drug Deliv Rev 58: 350-357 (“Burt 2006”); and Lusis A J (2000) Atherosclerosis, Nature 407: 233-241 (“Lusis 2000”). Three different processes have been identified in studies of animals with induced hypercholesterolaemia that are thought to participate in the formation of atherosclerotic lesions: 1) proliferation of smooth muscle cells, macrophages and lymphocytes; 2) the formation by smooth muscle cells of a connective tissue matrix comprising elastic fiber proteins, collagen and proteoglycans; and 3) accumulation of lipid and mostly free and esterified cholesterol in the surrounding matrix and the associated cells. See Ross R (1993), The pathogenesis of atherosclerosis: a perspective for the 1990s, Nature 362: 801-809.
The introductions of balloon angioplasty and stent implantation in the coronary arteries have reduced significantly the fatalities associated with this disease, however, coronary artery restenosis and neointimal hyperplasia remain clinical problems. See Lusis 2000; and Al Suwaidi J, Berger P B, Holmes D R, Jr. (2000) Coronary artery stents, Jama 284: 1828-1836. Millions of people are affected by atherosclerosis. One feature of this disease is stenosis, which is defined as an abnormal narrowing or contraction of a tubular body part such as arteries, veins, non-vascular ducts and other tubular structures such as urethra, fallopian tubes, esophageal, bronchial passages, and the like. Stenosis causes decreased blood flow through the vessel. A common treatment for stenosis is bypass surgery with less invasive procedures, such as angioplasty procedures like PTA (percutaneous transluminal angioplasty) also available. Angioplasty involves inserting a balloon catheter into the body to the location of the stenosis, then inflating the balloon against the lesion, and applying pressure to compress the lesion and widen or restore the inside diameter of the blood vessel to restore blood flow. Variations of PTA procedures have been used to treat peripheral arterial stenosis, coronary lesions and other non-vascular tubular structures such as biliary ducts.
Although PTA treatments find success in restoring blood flow, such success may be limited or temporary under certain circumstances. For instance, it has been found that anywhere from three to six months following the angioplasty procedure about half of those treated with PTA develop a re-narrowing or occlusion of the vessel, referred to as restenosis. While the original blockage is formed by plaque deposits on the vessel wall, restenosis is caused by growth of smooth muscle cells of the treated artery after angioplasty. It is the trauma imposed on the vessel wall during angioplasty itself that is the cause of restenosis. More particularly, the body reacts to the angioplasty procedure as an injury and produces scar tissue as cells regenerate on the inner wall of the blood vessel in response to the procedure. It is overgrowth of these cells that causes the restenosis, which is the recurrence of stenosis after the PTA procedure. A second angioplasty procedure or bypass are common treatments for restenosis, but each of these exposes the patient to additional risks. This is because the angioplasty procedure is often a temporary fix as it will retraumatize the vessel wall—resulting in the recurrence of smooth muscle cell proliferation. Adding further complexity to the issue, restenosis often presents itself asymmetrically, characterized by cellular regrowth on only portions of the circumference of the vessel wall. It has been found that eccentric and polypoid narrowings are not amenable to treatment with PTA alone. See Becker G J, Katzen B T, Dake M D, Noncoronary angioplasty, Radiology 1989; 170:921-940.
In attempts to limit the amount of restenosis after angioplasty, efforts have been made to reduce the trauma associated during treatment procedures for stenosis. Such efforts include using balloon catheters equipped for cutting or excising the lesions or in combination with an endomyocardial biopsy device. These efforts, however, have not proven any greater success over conventional angioplasty techniques in preventing restenosis after surgery.
Post-angioplasty approaches for reducing restenosis have also been pursued. One such technique involves implanting drug-eluting stents comprising compositions for suppressing the growth of scar tissue. These techniques have been known to reduce restenosis but are not preferred due to complications, such as localized blood clots after elution of the drug, stent fracture, or other long-term implant issues. Most notable risk factors with stents concern the arterial wall injury that is generated with the implantation of the stent and the pressure applied by the balloon. In-stent restenosis after bare-metal stent (BMS) placement results in an aggressive healing response (neointimal hyperplasia) that causes vascular narrowing. See Burt 2006; Legrand V (2007), Therapy insight: diabetes and drug-eluting stents, Nat Clin Pract Cardiovasc Med 4: 143-150; and Ward M R, Pasterkamp G, Yeung A C, Borst C (2000) Arterial remodeling, Mechanisms and clinical implications, Circulation 102: 1186-1191.
Still others have used angioplasty combined with a technique referred to as non-thermal irreversible electroporation. The IRE approach generally involves treatment of the cells subjected to angioplasty to a therapeutic electric field. The goal is to target the vascular cells to ablate and kill the cells without causing thermal or mechanical damage. This approach selectively kills the target cells while avoiding damage to the structure of the artery and surrounding tissue. Restenosis is thus avoided or reduced because the targeted vascular cells are killed, which then do not have the capability of forming scar tissue (neointimal).
Generally, irreversible electroporation (IRE) is a minimally invasive technique to ablate undesired tissue. See Davalos R V, Mir L M, Rubinsky B (2005), Tissue ablation with irreversible electroporation, Annals of Biomedical Engineering 33: 223-231 (“Davalos 2005”). Maor and colleagues showed that IRE reduces the vascular smooth muscle cells population of major blood vessels without affecting the extracellular matrix, which is crucial in the treatment of coronary artery disease. See Maor E, Ivorra A, Leor J, Rubinsky B (2007), The effect of irreversible electroporation on blood vessels, Technology in Cancer Research and Treatment 6: 307-312. The procedure involves delivering a series of low energy (intense but short) electric pulses to the targeted tissue. These pulses permanently destabilize the cell membranes of the treated tissue and cause cell death. IRE has been shown to be an effective means of tissue ablation that does not require drugs, and creates no secondary thermal effects thereby, preserves extracellular matrix, micro-vasculature and nerves. See Rubinsky B (2007), Irreversible Electroporation in Medicine, Technology in Cancer Research and Treatment 6: 255-260. Furthermore, IRE ablates tissue with sub-millimeter resolution and the treated area can be imaged in real-time using ultrasound, or other imaging techniques such as Magnetic Resonance Imaging, Computed Tomography and/or Intravascular Ultrasound (IVUS).
More particularly, as a result of being exposed to the IRE electric field, the pores of the target cells are opened to a degree beyond which they can recover and the cells die. Concerning restenosis in particular, with fewer cells remaining on the vascular wall after the angioplasty procedure, the cells are unable to grow thus preventing restenosis altogether, or the cells which are limited in number can only experience a limited amount of cellular regrowth thus reducing the amount of restenosis. IRE can be performed before, during, and/or after angioplasty. In some cases, the IRE is preferably performed before restenosis occurs, e.g., before angioplasty to treat tissue that will later be exposed to an angioplasty procedure.
It has been known to use IRE on blood vessels using plate electrodes placed around the carotid artery to apply the electric pulses. See Maor, E., A. Ivorra, J. Leor, and B. Rubinsky, The Effect of Irreversible Electroporation on Blood Vessels, Technol Cancer Res Treat, 2007, 6(4): p. 307-312; Maor, E., A. Ivorra, J. Leor, and B. Rubinsky, Irreversible electroporation attenuates neointimal formation after angioplasty, IEEE Trans Biomed Eng, 2008, 55(9): p. 2268-74; and Maor, E., A. Ivorra, and B. Rubinsky, Non Thermal Irreversible Electroporation: Novel Technology for Vascular Smooth Muscle Cells Ablation, PLoS ONE, 2009, 4(3): p. e4757. Unfortunately, this electrode design is highly invasive and requires the physical exposure of the targeted vessel in order to treat it.
In other existing IRE procedures for treatment of restenosis, the entire circumference of the vessel wall is exposed to the IRE electric field. In such designs it has been known to use an electrode with positive and negative independent conducting surfaces, which are energized in an all-or-nothing system, energizing the entire circumference of the electrode at the same time and with equal energy delivery. Such an approach is not desirable for cases of asymmetrical restenosis, however, where only a portion or less than the entire circumference of the vessel wall is diseased. In treating asymmetric restenosis with circumferential IRE, vascular cells on non-diseased portions of the vessel wall are unnecessarily destroyed.
Thus, it is apparent that there is a need for less invasive, less traumatic treatment procedures for treating, reducing, or preventing restenosis. Especially needed are procedures capable of targeting only the diseased portions of the vascular structure, or capable of targeting only portions of the vascular structure susceptible to restenosis, such as tissue previously subjected to stenosis treatment and/or stenotic tissue prior to treatment.